The pharmacologic basis of opiate tolerance and physical dependence development is being investigated in the mouse, rat and guinea pig. Attempts to validate an operational model for opiate action are based on established opiate-calcium interactions. It is proposed that there are two opposing effects of opiates on neuronal Ca ions: (a) an immediate effect to lower neuronal Ca ions and this is responsible for the acute responses to opiates, (b) a delayed effect which reflects a counteradaptive response to reverse the acute Ca ions lowering action of the opiate and this is responsible for the development of tolerance and physical dependence. In essence, the analgetic effects of opiates are related to a lowering of brain calcium at selective compartments in enriched nerve endings (synaptosomes). Tolerance is due to the accumulation of neuronal calcium that antagonizes acute opiate action. This effect is cumulative and its buildup is dependent on continuous opiate administration. The ability to oppose narcotic action becomes apparent only after there is sufficient accumulation of neuronal Ca ions to antagonize the acute effect of opiates. Physical dependence is due to a hyperexcitable state of the neuron caused by the elevated neuronal Ca ions; the state is masked by the presence of opiates and becomes manifest in its absence resulting in the abstinence syndrome. Calcium uptake experiments in enriched nerve endings (synaptosomes) will involve the use of opiate agonists (alkaloids and peptides), opiate antagonists (naloxone), calcium and cyclic nucleotides.